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US6673816B1 - Rhodanine carboxylic acid derivatives for the treatment and prevention of metabolic bone disorders - Google Patents

Rhodanine carboxylic acid derivatives for the treatment and prevention of metabolic bone disorders Download PDF

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Publication number
US6673816B1
US6673816B1 US09/787,917 US78791701A US6673816B1 US 6673816 B1 US6673816 B1 US 6673816B1 US 78791701 A US78791701 A US 78791701A US 6673816 B1 US6673816 B1 US 6673816B1
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Prior art keywords
oxo
thioxo
thiazolidin
signifies
acid
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Expired - Fee Related
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US09/787,917
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English (en)
Inventor
Angelika Esswein
Wolfgang Schaefer
Christos Tsaklakidis
Konrad Honold
Klaus Kaluza
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Assigned to SCHAFER, WOLFGANG, ESSWEIN, ANGELIKA, HONOLD, KONRAD reassignment SCHAFER, WOLFGANG ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: TSAKLAKIDIS, CHRISTOS, KALUZA, KLAUS
Priority to US10/199,057 priority Critical patent/US20030032813A1/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D277/36—Sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
    • C07D493/04—Ortho-condensed systems

Definitions

  • the present invention is concerned with rhodanine carboxylic acid derivatives for the treatment and prevention of metabolic bone disorders, a process for their manufacture as well as medicaments which contain these compounds.
  • bone resorption inhibitors such as oestrogens, calcitonin and biphosphonates have primarily been used for the treatment of metabolic bone disorders.
  • the use of these substances is, however, limited and also does not show the desired effect in all cases.
  • Compounds which have a stimulating activity on bone synthesis and in addition contribute to an increase in an already reduced bone mass are accordingly of especial significance for the treatment of metabolic bone disorders.
  • Compounds having the rhodanine carboxylic acid structural element are known as antidiabetics, cytostatics inflammation inhibitors and for the treatment of cardiovascular illnesses and bacterial infections.
  • the parathyroid hormone (PTH) is the natural ligand of the receptor and an important regulator for the maintenance of the calcium level in the body.
  • PTH can stimulate bone formation or bone resorption. In this, it acts as a regulatory hormone on a series of enzymes, inter alia, on adenylate cyclase (cAMP synthesis) and on ornithine decarboxylase.
  • cAMP synthesis adenylate cyclase
  • PTH mobilizes calcium from bones in the case of calcium deficiency, reduces calcium excretion from the kidneys and simultaneously improves the resorption of calcium from the intestine by an increased synthesis of 1,25—(OH) 2 D 3 .
  • a normalization of the calcium level is achieved by the action on these target organs.
  • rhodanine carboxylic acid derivatives of the present invention stimulate the PTH receptor-mediated cAMP formation.
  • Compounds of the present invention are accordingly suitable for the broad treatment of metabolic bone disorders. They can be used primarily to good effect where the bone synthesis is disturbed, i.e. they are especially suitable for the treatment of osteopenic disorders of the skeletal system such as e.g. osteoporosis, inter alia, osteogenesis imperfecta as well as for the local assistance in bone regeneration and osteoinduction such as e.g. in orthopedic and maxillary medical indications, in fracture healing, osteosyntheses, pseudoarthroses and for the healing in of bone implants.
  • osteoporosis e.g. osteoporosis
  • osteogenesis imperfecta e.g. in orthopedic and maxillary medical indications, in fracture healing, osteosyntheses, pseudoarthroses and for the healing in of bone implants.
  • osteoinduction e.g. in orthopedic and maxillary medical indications, in fracture healing, osteosyn
  • rhodanine carboxylic acid derivatives of the present invention as active substances furthermore form a basis for the local and systemic treatment of rheumatoid arthritis, osteoarthritis and degenerative arthrosis.
  • the object of the present invention are compounds of general formula (I),
  • n 0-8
  • q signifies a number between 0-8
  • a signifies a number between 0-4
  • A signifies a single or double bond
  • R 1 , R 2 signify hydrogen or lower alkyl, whereby R 1 and R 2 can be the same or different and, when m signifies 2-8, R 1 and R 2 in the group CR 1 ⁇ CR 2 can have various significances within the following sequence
  • R 3 signifies hydrogen or lower alkyl
  • Y signifies hydrogen, —COR 4 , phenyl or indolyl residue
  • R 4 signifies hydroxyl, lower alkoxy or the NR 1 R 2 residue, whereby R 1 and R 2 can be the same or different
  • W signifies an optionally mono- or polysubstituted saturated or unsaturated mono-, bi- or tricycle which can contain one or more hetero atoms
  • lower alkyl signifies linear or branched alkyl residues with one to six carbon atoms, preferably methyl, ethyl, propyl, i-propyl, butyl, t-butyl, pentyl, hexyl, particularly methyl.
  • Alkoxy groups signify a combination of a C 1 -C 10 -alkyl group in accordance with the above definition with an oxygen atom, e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy and pentoxy groups.
  • phenyl phenyl ether diphenylmethane and biphenyl.
  • Substituents are preferably lower alkyl, alkoxy, alkoxycarbonylalkyl, alkoxycarbonyl, acetylamino, alkoxydialkylamino, amino, dialkylamino, benzyl, benzyloxy, benzyloxybenzyloxy, carboxyl, chlorophenylsulphanyl, dioxymethylene, mercaptoalkyl, nitro, phenoxy, styryl and halogen.
  • this is preferably a residue such as the naphthyl, tetrahydronaphthyl, decalinyl, quinolinyl, chromane, chromene, isoquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, indolyl, benzimidazolyl, indazolyl, oxindolyl, benzofuranyl, benzothiophenyl, benzochiazolyl, benzoxazolyl or purinyl residue, especially the indolyl, naphthyl, benzimidazolyl, quinolinyl, tetrahydroquinolinyl benzothiophenyl and benzofuranyl residue, which optionally can be mono- or polysubstituted.
  • Substituents are preferably lower alkyl, alkoxy, alkoxycarbonylalkyl, alkoxycarbonyl, acetylamino, alkoxydialkylamino, amino, dialkylamino, benzyl, benzyloxy, benzyloxybenzyloxy, carboxyl, chlorophenylsulphanyl, dioxymethylene, mercaptoalkyl, nitro, phenoxy, styryl and halogen.
  • this is preferably a residue such as the anthracene, fluorene, dibenzofuran or carbazole.
  • n 0-8
  • q signifies a number between 0-8
  • a signifies a number between 0-4
  • A signifies a single or double bond
  • R 1 , R 2 signify hydrogen or lower alkyl, whereby R 1 and R 2 can be the same or different and, when m signifies 2-8, R 1 and R 2 in the group CR 1 ⁇ CR 2 can have various significances within the following sequence
  • R 3 signifies hydrogen or lower alkyl
  • Y signifies hydrogen, —COR 4 , phenyl or indolyl residue
  • R 4 signifies hydroxyl, lower alkoxy or the NR 1 R 2 residue, whereby R 1 and R 2 can be the same or different
  • W signifies an optionally mono- or polysubstituted saturated or unsaturated mono-, bi- or tricycle which can contain one or more hetero atoms
  • W is not phenyl or indolyl, if m and g are both 0, R 3 is hydrogen and A is a double bond, as well as their physiologically compatible salts, esters, optically active forms, racemates, tautomers, as well as derivatives which can be metabolized in vivo to compounds of general formula (I), as well as the use of these compounds for the production of medicaments.
  • Preferred are compounds of general formula I in which m signifies a number between 0 and 4, q signifes the number 0 or 1, a signifies a number of 0 to 4, A signifies a double bond, R 1,2 signify hydrogen or methyl, X signifies hydrogen or —(CH 2 ) b —COR 4 with b 0-2 and R 4 equals hydroxyl, methoxy or NR 1 R 2 , Y signifies hydrogen or COR 4 , the phenyl or indolyl residue, R 3 signifies hydrogen or methyl and W signifies an optionally mono- or polysubstituted benzothiophene, phenyl, benzofuran, thiophene, naphthalene, piperidine, cyclohexenyl or biphenyl residue.
  • rhodanine carboxylic acids and aldehydes used as starting materials are either commercially available, known or can be prepared analogously to the generally known processes.
  • Compounds of formula (I) can be administered (sic) in liquid, solid or aerosol form orally, enterally, parenterally, topically, nasally, pulmonary or rectally in all usual non-toxic pharmaceutically acceptable carrier materials, adjuvants and additives.
  • the compounds of formula (I) can also be applied locally to/in the bones (optionally with surgical intervention).
  • parenteral embraces subcutaneous, intravenous and intramuscular delivery or infusions.
  • Oral administration forms can be e.g. tablets, capsules, dragees, syrups, solutions, suspensions, emulsions, elixirs etc., which can contain one or more additives from the following groups, such as flavourings, sweeteners, colouring agents and preservatives.
  • Oral administration forms contain the active ingredient together with non-toxic, pharmaceutically acceptable carrier materials which are suitable for the production of tablets, capsules, dragees etc., such as e.g., calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; starch, mannitol, methylcellulose, talc, highly dispersible silicic acids, high molecular fatty acids (such as stearic acid), groundnut oil, olive oil, paraffin, miglyol, gelatine, agar-agar, magnesium stearate, beeswax, cetyl alcohol, lecithin, glycerol, animal and vegetable fats, solid high molecular polymers (such as polyethylene glycol).
  • carrier materials which are suitable for the production of tablets, capsules, dragees etc., such as e.g., calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; starch, mannitol, methylcellulose
  • Tablets, capsules, dragees etc. can be provided with an appropriate coating, e.g. glyceryl monostearate or glyceryl distearate, in order to prevent undesired side effects in the gastrointestinal tract or to give a longer duration of action by the delayed absorption in the gastrointestinal tract.
  • an appropriate coating e.g. glyceryl monostearate or glyceryl distearate
  • sterile injectable aqueous or oily solutions or suspensions which contain the usual additives such as stabilizers and solubilizers.
  • additives can be e.g. water, isotonic saline, 1,3-butanediol, fatty acids (such as oleic acid), mono- and diglycerides or miglyol.
  • non-irritating additives which are solid at normal temperatures and liquid at rectal temperatures, such as e.g. cocoa butter and polyethylene glycol.
  • Pharmaceutically usual carrier media are used for application as aerosols. Creams, tinctures, gels, solutions or suspensions etc. with the pharmaceutically usual additives are used for external application.
  • the dosage can depend n a variety of factors such as mode of administration, species, age and/or individual condition.
  • the doses to be administered daily or at intervals lie at 1-1000 mg/individual, preferably at 10-250 mg/individual, and can be taken at one time or divided over several times.
  • the compounds of formula (I) can also be applied locally to/in the bones (optionally with surgical intervention).
  • the application directly to/in the bones (optionally with surgical intervention) can be effected locally or carrier-bonded either in solution or suspension, conveniently by infusion or injection.
  • Carrier-bonded compounds of formula (I) can be administered, for example, as gels, pastes, solids or as a coating on implants.
  • Biocompatible and preferably biodegradable materials are used as the carrier. Preferably, the materials themselves also induce wound healing or osteogenesis.
  • the compounds of formula (I) are imbedded in polymer gels or films in order to immobilize them and to apply these preparations directly on the site of the bone to be treated.
  • polymer-based gels or films consist, for example, of glycerine, methylcellulose, hyaluronic acid, polyethylene oxides and/or poloxamers.
  • collagen, gelatines and alginates are described, for example, in WO 93/00050 and WO 93/20859.
  • Further polymers are polylactic acid (PLA) and copolymers of lactic acid and glycolic acid (PLPG) (Hollinger el al., J. Biomed. Mater. Res.
  • DBM Demineralized Bone Matrix
  • polymers as are used, for example, for the adsorption of TGF ⁇ and which are described in EP-A 0 616 814 and EP-A-0 567 391 and synthetic bone matrices in accordance with WO 91/18558.
  • suitable as carriers for the compounds of formula (I) are materials which are usually used for the implantation of bone substitutes or otherwise of therapeutically active substances. Such carriers are based, for example, on calcium sulphate, tricalcium phosphate, hydroxylapatite (sic) and its biodegradable derivatives and polyanhydrides. Apart from these biodegradable carriers there are also suitable carriers which are not biodegradable, but which are biocompatible. Such carriers are, for example, sintered hydroxylapatite, bioglass, aluminates or other ceramic materials (e.g. calcium aluminium phosphate). These materials are preferably used in combination with the biodegradable materials, such as especially polylactic acid, hydroxylapatite, collagen or tricalcium phosphate. Further non-degradable carriers are described, for example, in U.S. Pat. No. 4,164,560.
  • a carrier which liberates the compounds of formula (I) continuously at the target site is especially preferred.
  • a carrier which liberates the compounds of formula (I) continuously at the target site are especially suitable for this.
  • Preferred in the scope of the present invention are, apart form the compounds named in the Examples and compounds derivable by a combination of all of the significances of the substituents set forth in the claims, the following derivatives as well as their physiologically compatible salts, esters, optically active forms, racemates, tautomers as well as derivatives which can be metabolized in vivo to compounds of general formula (I), as well as the use of these compounds for the production of medicaments.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Physical Education & Sports Medicine (AREA)
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  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Thiazole And Isothizaole Compounds (AREA)
US09/787,917 1998-09-30 1999-09-30 Rhodanine carboxylic acid derivatives for the treatment and prevention of metabolic bone disorders Expired - Fee Related US6673816B1 (en)

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US10/199,057 US20030032813A1 (en) 1998-09-30 2002-07-22 Rhodanine carboxylic acid derivatives for the treatment and prevention of metabolic bone disorders

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EP98118493 1998-09-30
EP98118493 1998-09-30
PCT/EP1999/007248 WO2000018747A1 (fr) 1998-09-30 1999-09-30 Derives d'acide carboxylique de rhodanine utiles pour le traitement et la prevention de troubles metaboliques des os

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US10/199,057 Abandoned US20030032813A1 (en) 1998-09-30 2002-07-22 Rhodanine carboxylic acid derivatives for the treatment and prevention of metabolic bone disorders

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US (2) US6673816B1 (fr)
EP (1) EP1117655A1 (fr)
JP (1) JP2002525362A (fr)
AU (1) AU6330799A (fr)
WO (1) WO2000018747A1 (fr)

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US20070203188A1 (en) * 2006-02-17 2007-08-30 University Of Pittsburgh Low molecular weight Myc-Max inhibitors
US9005660B2 (en) 2009-02-06 2015-04-14 Egalet Ltd. Immediate release composition resistant to abuse by intake of alcohol
US9023394B2 (en) 2009-06-24 2015-05-05 Egalet Ltd. Formulations and methods for the controlled release of active drug substances
US9056862B2 (en) 2011-05-10 2015-06-16 National University Corporation Kobe University Thioxothiazolidine derivative having Ras function inhibitory effect
US9375428B2 (en) 2003-03-26 2016-06-28 Egalet Ltd. Morphine controlled release system
US9642809B2 (en) 2007-06-04 2017-05-09 Egalet Ltd. Controlled release pharmaceutical compositions for prolonged effect

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CA2374616A1 (fr) * 1999-06-10 2000-12-21 Warner-Lambert Company Derives de rhodanine utilises dans un procede d'inhibition de l'agregation de proteines amyloides et de formation d'images de depots amyloides
US6506755B2 (en) * 2000-02-03 2003-01-14 Hoffmann-La Roche Inc. Thiazolidinecarboxyl acids
GB0021419D0 (en) 2000-08-31 2000-10-18 Oxford Glycosciences Uk Ltd Compounds
GB0021421D0 (en) * 2000-08-31 2000-10-18 Oxford Glycosciences Uk Ltd Compounds
GB2386892A (en) * 2002-03-28 2003-10-01 Pantherix Ltd Carboxy containing (phenyl-/heterocyclyl-)methylene substituted azole & azine derivatives and their therapeutic use as antibacterials
NZ563846A (en) * 2005-06-03 2010-03-26 Egalet As A drug delivery system for delivering active substances dispersed in a dispersion medium
CN106045987B (zh) * 2016-06-21 2019-04-23 广东工业大学 一种具有多功能近红外荧光磁性纳米微粒及其制备和应用
EP3404022B1 (fr) * 2017-05-19 2020-10-07 Paris Sciences et Lettres - Quartier Latin Chromophores fluorogènes imperméants aux membranes
RU2768456C2 (ru) * 2019-07-11 2022-03-24 Общество С Ограниченной Ответственностью "Научно-Исследовательский Центр "Парк Активных Молекул" (Ооо "Ниц Пам") Применение производного роданина 3-(2-фенилэтил)-2-тиоксо-1,3 тиазолидин-4-она для нормализации обмена веществ, повышения неспецифической резистентности, роста и развития животных
RU2768171C2 (ru) * 2019-07-11 2022-03-23 Общество С Ограниченной Ответственностью "Научно-Исследовательский Центр "Парк Активных Молекул" (Ооо "Ниц Пам") Применение производного роданина 3-(2 -фенилэтил)-2-тиоксо-1,3 тиазолидин-4-она для коррекции нарушений обмена веществ

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EP0047109B1 (fr) 1980-08-22 1985-01-02 Ono Pharmaceutical Co., Ltd. Dérivés de rhodanine, leur préparation et inhibiteurs aldose-reductase qui les contiennent
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EP0237138A1 (fr) 1986-01-07 1987-09-16 Yamanouchi Pharmaceutical Co., Ltd. Composés hétérocycliques, leur préparation et compositions pharmaceutiques les contenant
EP0291007A1 (fr) 1987-05-11 1988-11-17 Kaken Pharmaceutical Co., Ltd. Dérivés de rhodanines, procédé de préparation et compositions pharmaceutiques les contenant
EP0343643A2 (fr) 1988-05-25 1989-11-29 Warner-Lambert Company Dérivés arylméthyléniques, sélectionnés de thiazolidinones, d'imidazolidinones et d'oxazolidinones utiles comme agents anti-allergiques et comme agents anti-inflammatoires
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US9375428B2 (en) 2003-03-26 2016-06-28 Egalet Ltd. Morphine controlled release system
US9884029B2 (en) 2003-03-26 2018-02-06 Egalet Ltd. Morphine controlled release system
US20070203188A1 (en) * 2006-02-17 2007-08-30 University Of Pittsburgh Low molecular weight Myc-Max inhibitors
US7872027B2 (en) * 2006-02-17 2011-01-18 University Of Pittsburgh - Of The Commonwealth System Of Higher Education Low molecular weight Myc-max inhibitors
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US9005660B2 (en) 2009-02-06 2015-04-14 Egalet Ltd. Immediate release composition resistant to abuse by intake of alcohol
US9358295B2 (en) 2009-02-06 2016-06-07 Egalet Ltd. Immediate release composition resistant to abuse by intake of alcohol
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US9056862B2 (en) 2011-05-10 2015-06-16 National University Corporation Kobe University Thioxothiazolidine derivative having Ras function inhibitory effect

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AU6330799A (en) 2000-04-17

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